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Introduction

The establishment of breast screening programs in the UK, Australia, and New Zealand resulted in an increase in the diagnosis of ductal carcinoma in situ (DCIS). At that time, randomized trials had demonstrated that breast conservation therapy (BCT) for invasive cancer was a safe alternative to mastectomy. However, it was still unclear whether breast-conserving alternatives were sufficient for DCIS. This study (contemporary with NSABP B-17, EORTC 10853, and NSABP B-24) was designed to investigate the role of breast irradiation as well as adjuvant tamoxifen for locally excised DCIS.

Methods

Between 1990 and 1998, patients with DCIS and microinvasive carcinoma detected by screening and deemed suitable for BCT were offered participation

The study excluded patients with lobular carcinoma in situ, uncertain pathological margins of resection, Paget's disease, and reduced life expectancy

Complete excision, defined by free margins on histological examination and radiology of the surgical specimen, was required

Re-excision was allowed to establish clear margins

Randomization, using a 2x2 factorial design, was independent for each of the two treatments (radiotherapy and tamoxifen)

Patients who either expressed a preference within one of the 2-way randomizations or were not equally suitable for the options within one of the randomizations were only randomized and analyzed on the other 2-way pathway

Radiotherapy consisted of supervoltage radiation to the whole breast through tangential fields to a dose of 50 Gy (at isocenter) in 25 fractions over 5 weeks

Tamoxifen was prescribed at a dose of 20 mg daily for 5 years

Patients were followed up at least once a year

Analysis was confined to patients who were randomly allocated to each main treatment comparison

All analyses were on an intention-to-treat basis and stratified according with whether the alternate treatment had been given or not, and whether this was by choice or because of random treatment

All p values are two-sided

Results

1694 patients were analyzed (1701 entered minus 7 excluded):

912 participated in the 2x2 randomization

782 refused randomization in one of the 2-way pathways:

664 chose whether or not to have radiation, with 603 choosing no radiation. They only participated in the tamoxifen randomization.

118 chose whether or not to have tamoxifen, with 29 choosing no tamoxifen. They only participated in the radiation randomization.

Median follow-up was 52.6 months

3% had micro-invasion and 8% were on HRT (well balanced among arms)

Recurrence in these subgroups did not differ from that in the overall group

10% were younger than 50 years at randomization

16% developed new breast events (9% in situ and 6% invasive)

85% of these were ipsilateral

The event rate per 100 woman-years was highest in the group who received no adjuvant treatment (4.77), and second highest in the group who received tamoxifen only (3.86)

Women who received radiotherapy had the lowest event rates

1576 were randomized/analyzed for the tamoxifen comparison: 782 controls and 794 in the treated group

New breast events were noted in 14% of patients randomized to tamoxifen and 18% in those randomized to no tamoxifen (not significant)

Invasive events: 7% vs. 6% (not significant)

In situ events: 7% vs. 11% (less with tamoxifen, p=0?03)

There were too few contralateral events for analysis

1030 were randomized/analyzed for the radiotherapy comparison: 508 patients in the control group and 522 in the treated group

New breast events were noted in 7% of patients randomized to radiotherapy and 16% in those randomized to no radiotherapy (highly significant reduction with radiotherapy)

8 were gynecological tumors; 7 among those who had tamoxifen and 1 among those who did not have tamoxifen (not significant)

45 patients died during follow-up:

In 23 the cause of death was breast cancer

There were too few deaths for comparison between treatment arms

With respect to the occurrence of new events, the effect of tamoxifen was not altered by radiotherapy and vice-versa

Because only 160 (9.5%) patients were younger than 50 years at randomization, meaningful analysis of the effect of radiotherapy and tamoxifen stratified by age (=50 years vs. >50 years) was not possible

Discussion

Ipsilateral invasive disease was not reduced by tamoxifen.

The only significant reduction associated with tamoxifen in the absence of radiotherapy was in the rate of ipsilateral DCIS.

For patients who also received radiotherapy, the reduction in these events was not significant.

These results differ from the only other trial to investigate this drug in completely excised DCIS:

In the NSABP B-24 trial, the number of new breast events was significantly lower in the tamoxifen group than in the control group

Dec 9, 2010 - A long-term follow-up study has confirmed the effectiveness of radiotherapy in reducing the incidence of ipsilateral breast events and found that tamoxifen has a role in preventing local and contralateral new breast events for women with ductal carcinoma in situ. The research has been published online Dec. 8 in The Lancet Oncology.